Project Summary/Abstract Deficient control and monitoring of memory processes is a key feature of major psychiatric diseases, including schizophrenia, bipolar disorder, and PTSD. The long-term goal of this research is to understand how individual brain areas within the temporal-and frontal lobes interact, how these interactions are coordinated and how disruption of such coordination results in mental disease. The proposed experiments will utilize rare neurosurgical opportunities to directly record from individual neurons in several areas of the human medial frontal cortex and the hippocampus to study the role of theta-mediated coordination in the executive control of memory. This approach is motivated by previous work from this laboratory, which has revealed a candidate microcircuit for declarative memories consisting of groups of cells that signal memory strength and a second group that signals highly processed sensory information independent of memories (VS/MS neurons). The overall objective of this application is to understand how information provided by these hippocampal neurons is utilized by areas in the medial frontal lobes to make decisions and how such memory-based decision making processes are monitored and controlled. We will achieve this objective by recording single-neurons from the hippocampus and three medial frontal cortical areas important for monitoring and control of memory processes: the ACC, pre-SMA, and vmPFC. Our central hypothesis is that Frontal-Hippocampal coordination is mediated by theta-band oscillations such that subsets of medial frontal neurons transiently phase-lock to hippocampal theta oscillations in order to gain access to task-relevant information provided by subsets of VS/MS neurons in the hippocampus. Our specific aims are to determine how medial frontal neurons accumulate evidence provided by the hippocampus (Aim 1), to determine whether medial frontal neurons exert top-down control over the hippocampus (Aim 2), and to test the causality of theta-mediated medial frontal- hippocampal coordination for memory (Aim 3). The contribution is significant because it will provide an unprecedented characterization of the role of medial frontal-hippocampal coordination in the control of memory processes through bottom-up and top-down interactions and their causal necessity. The approach is innovative because we directly test, in humans, a hypothesis of high significance for psychiatric disease which cannot be tested by non-invasive fMRI/EEG/MEG studies nor by animal models due to the unclear homologies of frontal areas. The work proposed in this application will advance knowledge on the normal mechanisms of frontal- temporal coordination by theta oscillations and might thereby enable the development of new treatments to restore or improve such coordination in cases of mental disease.